PROJECT SUMMARY: Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia after Alzheimer's disease (AD) in patients <65 years of age. Tau and TDP-43 pathology variants of FTLD (FTLD-Tau and FTLD-TDP, respectively) account for -90 of FTLD cases, but TDP-43 pathology occurs in >50% of patients with AD, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and Guam amyotrophic lateral sclerosis (ALS)/Parkinson Dementia Complex (ALS/PDC). Despite the fact that this neuropathology overlap is well known, it is unclear how comorbid Ap, tau and alpha-synuclein pathology modify TDP-43 mediated neurodegeneration in patients with frontotemporal dementia (FTD). Conversely, it is unknown how TDP-43 modifies Ap, tau and alpha-synuclein pathologies, but TDP-43 pathology is known to independently contribute to behavioral impairments in AD. Since these issues are tractable to investigate experimentally in transgenic (Tg) mouse models of TDP-43, tau, Ap and alpha-synuclein pathology. Project 4 tests the hypothesis that comorbid tau, Ap and alpha-synuclein pathologies in Tg mice independently modify TDP-43 mediated neurodegeneration and wee versa. This will be done by studying TDP-43 Tg mice which recapitulate the hallmark features of FTLD-TDP that we cross with our previously characterized mutant P301S tau Tg mice which show tau mediated neurodegeneration, behavioral impairments and premature death, Tg2576 Tg mice that model AD-like Ap pathology and our extensively studied M83 alpha-synuclien Tg mice that develop Lewy body pathology, motor impairments and lethal neurodegeneration. Implementing these Aims will elucidate how TDP-43 mediated neurodegenerative disease is modified by comorbid tau, Ap and alpha-synuclien pathologies and vice versa. These studies are highly significant because they will clarify mechanisms of TDP-43 proteinopathy and they have translational potential to improve both the diagnosis and the treatment of patients with TDP-43 proteinopathy.